On February 14, 2022 Taiho Pharmaceutical Co., Ltd. reported that it has submitted to the Japanese Ministry of Health, Labour and Welfare, an application for the additional indication of "postoperative adjuvant chemotherapy in breast cancer" for its oral anticancer agent TS-1 (Press release, Taiho, FEB 14, 2022, View Source [SID1234608061]).

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This application is based on the results of an investigator-initiated study, Postoperative Therapy with TS-1 for oestrogen receptor-positive, HER2-negative breast cancer (POTENT study). According to the results of the POTENT study, the combination of TS-1 with endocrine therapy showed a clinically significant extension of invasive disease-free survival (iDFS) among patients with oestrogen receptor-positive, HER2-negative breast cancer with an intermediate or higher risk of recurrence. The safety profile was similar to that of TS-1 reported in the past, and no new concerns were identified in the POTENT study.

Taiho Pharmaceutical will continue to prepare for the delivery of this treatment option to patients with breast cancer, aiming to obtain approval as quickly as possible.

About the POTENT Study
POTENT is an investigator-initiated study conducted since March 25, 2011, under the designation of advanced medical care (Specific Clinical Research jRCTs051180057，UMIN000003969). The principal investigator, Masakazu Toi, M.D., Ph.D., Professor of Breast Surgery at Kyoto University’s Graduate School of Medicine and Faculty of Medicine, had submitted a study application to the Japanese Ministry of Health, Labour and Welfare under the former Advanced Medical Care Program. On January 25, 2011, the Advanced Medical Care Assessment Council approved the study with the advanced medical care name, "Postoperative Therapy with TS-1 for oestrogen receptor-positive, HER2-negative breast cancer."

The purpose of the study was to verify any increase in the effect on prevention of recurrence through a randomized comparative Phase III study in postoperative adjuvant therapy for oestrogen receptor-positive, HER2-negative breast cancer. The control group was treated with endocrine therapy (5 years), the standard treatment method, with the study group treated with endocrine therapy (5 years) in combination with TS-1 (1 year). The study endpoints included invasive disease-free survival, overall survival, safety, etc. The study enrolled 1,959 women from 139 breast cancer facilities across Japan during the registration period from February 2012 to February 2016.1

Public Health Research Center, contracted to serve as the study management office, received funding from Taiho Pharmaceutical and this study was conducted with such funding.
.

1 Toi M et al., Lancet Oncol 2021; 22: 74–84.

For more information of the POTENT study, please refer to
View Source
View Source (in Japanese only)

About Primary Breast Cancer
According to the Japan Breast Cancer Society’s Annual Report of the Japanese Breast Cancer Registry for 2017,2 94,612 women in Japan are affected by breast cancer annually. It is reported that 75.3% of these cases are oestrogen receptor-positive, HER2-negative breast cancer. In cases of early-stage breast cancer, perioperative chemotherapy and postoperative endocrine therapy are given as standard treatments in addition to surgery, considering the risk of recurrence.

2 Hayashi N et al., Breast Cancer 2020; 27:803–809.

About TS-1
A member of the fluoropyrimidine class of anticancer agents, TS-1 is a combination of three pharmacological compounds: tegafur, an antimetabolite agent that, after absorption, is converted into the anticancer agent fluorouracil (5-FU); gimeracil (5-chloro-2, 4-dihydroxypyridine, or CDHP), which decreases the degradation of 5-FU in the liver; and oteracil (Oxo), which decreases 5-FU phosphorylation in the gastrointestinal tract. Developed as a gastric cancer treatment, TS-1 was first approved in Japan in 1999 and has become a standard of care for the treatment of gastric cancer. TS-1 has been approved in Japan for the treatment of gastric, colorectal, head and neck, non-small cell lung, inoperable or recurrent breast, pancreatic, and biliary tract cancers.

On February 14, 2022 Arvinas, Inc. (Nasdaq: ARVN), a clinical-stage biotechnology company creating a new class of drugs based on targeted protein degradation, reported the presentation of new data showing that bavdegalutamide (also known as ARV-110), a novel PROTAC protein degrader targeting the androgen receptor (AR), continues to provide evidence of anti-tumor activity and patient benefit in metastatic castration-resistant prostate cancer (mCRPC) (Press release, Arvinas, FEB 14, 2022, View Source [SID1234608077]). These data show that bavdegalutamide reduced prostate-specific antigen (PSA) levels greater than or equal to 50% (PSA50) in 46% of patients with tumors harboring AR T878X/H875Y (T878X = T878A or T878S) mutations. Updated Phase 1 and interim Phase 2 ARDENT data will be presented in both a rapid abstract session and a poster session on February 17, 2022, at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Genitourinary (ASCO GU) Cancers Symposium.

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"These results are very encouraging and reinforce our conviction that bavdegalutamide has the potential to provide meaningful clinical benefit to patients with mCRPC who have progressed after treatment with novel hormonal agents and for whom few treatment options exist," said John Houston, Ph.D., president and chief executive officer of Arvinas. "With particularly robust activity in a molecularly defined patient population, we believe there is a clear path forward to developing this novel treatment as a precision medicine and plan to initiate a pivotal trial by year end 2022."

Highlights from the bavdegalutamide abstract (data cut-off date August 26, 2021):

Across 140 biomarker-evaluable patients with ≥1 month of PSA follow-up in the completed Phase 1 dose escalation and ongoing Phase 2 ARDENT expansion cohort:

Evidence of anti-tumor activity and patient benefit, including:
PSA50 rate of 46% in patients with AR T878X/H875Y tumor mutations (n=26)
Two confirmed RECIST (Response Evaluation Criteria in Solid Tumors) partial responses out of seven RECIST-evaluable patients with AR T878X/H875Y tumor mutations
PSA50 rate of 26% (five of 19) in evaluable patients in the subgroup defined as "less pretreated" (having received only one prior novel hormonal agent and no prior chemotherapy). The "less pretreated" subgroup had a similar circulating tumor DNA molecular profile to the more pretreated, biomarker-defined subgroups in the ARDENT trial; a majority of patients with PSA50 declines in this group had tumors with the AR T878X/H875Y mutations
Bavdegalutamide had a manageable tolerability profile at the recommended Phase 2 dose (RP2D) of 420 mg. The majority of treatment-related adverse events (TRAEs) were Grade 1/2 and there were no Grade ≥4 TRAEs in the 113 patients treated at the RP2D.
The most common TRAEs of any grade at the RP2D across Phase 1 and the ongoing phase 2 ARDENT expansion cohort were nausea (Grade 1/2: 42%; Grade 3: 1%), fatigue (Grade 1/2: 27%; Grade 3: 1%), vomiting (Grade 1/2: 23%; Grade 3: 1%), decreased appetite (Grade 1/2: 19%; Grade 3: 0), diarrhea (Grade 1/2: 15%; Grade 3: 2%), and alopecia (Grade 1/2: 11%).
"Novel hormonal agents have become standard of care in castration-sensitive prostate cancer and there is a need for novel AR therapies with the potential to provide benefit for patients with mCRPC and tumors that have developed resistance," said Ron Peck, M.D., chief medical officer at Arvinas. "As an oncologist, I’m particularly excited by a precision medicine approach with the potential to identify patients who are most likely to respond to bavdegalutamide."

Additional data from the completed Phase 1 and interim results from the ongoing Phase 2 ARDENT trial will be presented on Thursday, February 17, 2022. The cut-off date for data in the rapid abstract session and the poster session was December 20, 2021.

Poster presentation:

Poster Title: Phase 1/2 study of ARV-110, an androgen receptor (AR) PROTAC degrader, in metastatic castration-resistant prostate cancer (mCRPC)
Session: Poster Session A: Prostate Cancer
Date: Thursday, February 17, 2022
Time: 2:30 – 4:00 p.m. ET
Rapid abstract session (7:45 – 8:45 p.m. ET):

Rapid Abstract Title: Rapid Abstract Session A: Prostate Cancer
Date: Thursday, February 17, 2022
Time: 7:55 – 8:00 p.m. ET
The full abstract can be found at the official ASCO (Free ASCO Whitepaper) Genitourinary Cancers Symposium website here.

Arvinas Webcast Investor Meeting
Arvinas will host a conference call and webcast Thursday, February 17, 2022, at 8:30 a.m. ET, to discuss the completed Phase 1 dose escalation data and interim data from the Phase 2 ARDENT trial presented at ASCO (Free ASCO Whitepaper) GU. Participants are invited to listen by dialing (844) 467-7654 (domestic) or (602) 563-8497 (international) five minutes prior to the start of the call and providing the passcode 1085203.

Supporting materials for the conference call and webcast will be available on the Arvinas’ website at www.arvinas.com under Events + Presentations. A replay of the webcast will be archived on the Arvinas website following the presentation.

About Bavdegalutamide (ARV-110)

Bavdegalutamide is an investigational orally bioavailable PROTAC protein degrader designed to selectively target and degrade the androgen receptor (AR). Bavdegalutamide is being developed as a potential treatment for men with metastatic castration-resistant prostate cancer.

Bavdegalutamide has demonstrated activity in preclinical models of AR mutation or overexpression, both common mechanisms of resistance to currently available AR-targeted therapies.

On February 14, 2022 The Janssen Pharmaceutical Companies of Johnson & Johnson reported initial results from the Phase 3 MAGNITUDE study evaluating the investigational use of niraparib, a selective poly-ADP ribose polymerase (PARP) inhibitor, in combination with abiraterone acetate plus prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) with or without specific homologous recombination repair (HRR) gene alterations (Press release, Johnson & Johnson, FEB 14, 2022, View Source [SID1234608095]). At the final analysis for radiographic progression-free survival (rPFS), the treatment combination of niraparib and abiraterone acetate plus prednisone demonstrated a statistically significant improvement in patients with HRR gene alterations. Results will be featured in a late-breaking oral presentation (Abstract #12; Oral Abstract Session A) at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper)’s Genitourinary (ASCO GU) Cancers Symposium, taking place in San Francisco and virtually from February 17-19, 2022.

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MAGNITUDE (NCT03748641) is a Phase 3, randomized, double-blind, placebo-controlled, multicenter study evaluating the safety and efficacy of the combination of niraparib and abiraterone acetate plus prednisone as a first-line therapy in patients with mCRPC. The MAGNITUDE study was intentionally designed with two independent cohorts to assess treatment effect in patients with and without HRR gene alterations (including ATM, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, HDAC2, PALB2 alterations) versus standard of care. The cohort of patients with prospectively-identified HRR gene alterations enrolled 423 patients, with patients randomized to receive the combination of niraparib and abiraterone acetate plus prednisone (combination arm [n=212]) or placebo and abiraterone acetate plus prednisone (control arm [n=211]). At 18.6-month median follow-up, patients in the combination arm of the cohort with HRR gene alterations showed a significant improvement in rPFS, with a reduction in the risk of progression or death of 27 percent (hazard ratio [HR] 0.73; p=0.022). This improvement was most pronounced in patients with BRCA1/2 gene alterations, where a 47 percent risk reduction was observed for rPFS (HR 0.53; p=0.001), as analyzed by blinded independent central review (BICR). A consistent but greater improvement was observed in investigator-assessed rPFS, which showed an overall 36 percent risk reduction in patients with HRR gene alterations (HR: 0.64; p=0.002), and a 50 percent risk reduction in patients with BRCA1/2 gene alterations (HR: 0.50; p=0.0006).1

The cohort without HRR gene alterations (n=233) met the predefined futility criteria in August 2020, showing no benefit from the treatment combination (HR>1) in the HRR biomarker negative population.1 Enrollment into this cohort was stopped at the time of futility at the recommendation of the Independent Data Monitoring Committee. Investigators and patients were unblinded and given the opportunity to continue treatment with niraparib and abiraterone acetate plus prednisone or receive only abiraterone acetate plus prednisone at the discretion of the study investigator.

"When choosing a treatment plan for patients with prostate cancer, physicians must consider individual needs, particularly for patients with mCRPC with HRR gene alterations who face a poor prognosis," said Dr. Kim Chi, Medical Oncologist at BC Cancer – Vancouver and principal investigator of the MAGNITUDE study.* "The MAGNITUDE data provide important context about the subgroup of patients with prostate cancer who may benefit from treatment with niraparib in combination with abiraterone acetate plus prednisone in the first-line setting, as well as those who may be better served by other treatment options."

In patients with HRR gene alterations, clinically relevant improvements in outcomes were also seen at this first interim analysis for secondary endpoints including time to initiation of cytotoxic chemotherapy, time to symptomatic progression and time to PSA progression. Additionally, objective response rate was improved by the combination of niraparib and abiraterone acetate plus prednisone. Overall survival data were immature at this interim analysis and follow-up will continue for all secondary endpoints.1

"These data suggest clinically meaningful improvements in outcomes in patients with prostate with HRR gene alterations who may derive benefit from this combination regimen, highlighting the importance of biomarkers to guide the patient selection process," said Mary Guckert, RN, MSN, Vice President, Development Leader, Prostate Cancer, Janssen Research & Development, LLC. "The design of this trial aligns with the real-world setting as it includes patients with prostate cancer who were able to start first-line standard of care treatment, while awaiting HRR biomarker results, and shows the need to prospectively test for and identify patients most likey to benefit from the combination of niraparib and abiraterone acetate with prednisone."

The observed safety profile of the combination of niraparib and abiraterone acetate plus prednisone was consistent with the known safety profile of each agent. Of the patients with HRR gene alterations, 67 percent experienced Grade 3 adverse events (AEs) and 46.4 percent experienced Grade 4 AEs, largely driven by anemia and fatigue. Discontinuation rates for the combination arm and control arm were 10.8 percent and 4.7 percent respectively. The combination of niraparib and abiraterone acetate plus prednisone also maintained overall quality of life in comparison with placebo and abiraterone acetate plus prednisone as measured on the Functional Assessment of Cancer Therapy–Prostate (FACT-P) scale.1

Patients with HRR gene alterations, such as BRCA1/2, are at an increased risk of developing prostate cancer, and BRCA-related prostate cancer is usually aggressive.2 Long-term survival is low for patients with mCRPC and those who have HRR gene alterations face a worse prognosis, driving a significant unmet medical need for novel therapies in this disease.3,4

About MAGNITUDE
MAGNITUDE is a Phase 3 randomized, double-blind, placebo-controlled, multicenter clinical study evaluating the safety and efficacy of the combination of niraparib and abiraterone acetate plus prednisone as a first-line therapy for patients with mCRPC, with or without certain HRR gene alterations. The study includes two cohorts in which patients were randomized to receive either niraparib and abiraterone acetate plus prednisone or abiraterone acetate (placebo) plus prednisone cohorts: one cohort of patients with predefined HRR gene alterations (including ATM, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, HDAC2, PALB2 alterations) and one cohort of patients without HRR gene alterations. In a third, open-label cohort, all patients received a combination tablet of niraparib and abiraterone and a separate tablet of prednisone. The primary endpoint of the MAGNITUDE trial is rPFS. Secondary endpoints include time-to-initiation of cytotoxic chemotherapy, time to symptomatic progression, and overall survival.

About Niraparib
Niraparib is an orally administered, selective poly-ADP ribose polymerase (PARP) inhibitor, that is currently being studied by Janssen for the treatment of patients with prostate cancer. Additional ongoing studies include the Phase 3 AMPLITUDE study evaluating the combination of niraparib and abiraterone acetate plus prednisone in a biomarker-selected patient population with metastatic castration-sensitive prostate cancer and QUEST, a Phase 1b/2 study of niraparib combination therapies for the treatment of mCRPC.

In April 2016, Janssen Biotech, Inc. entered a worldwide (except Japan) collaboration and license agreement with TESARO, Inc. (acquired by GSK in 2018), for exclusive rights to niraparib in prostate cancer. In the U.S., niraparib is indicated for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in a complete or partial response to first-line platinum-based chemotherapy; for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy; for the treatment of adult patients with advanced ovarian, fallopian tube or primary peritoneal cancer who have been treated with three or more prior chemotherapy regimens and whose cancer is associated with homologous recombination deficiency (HRD) positive status defined by either: a deleterious or suspected deleterious BRCA mutation, or genomic instability and who have progressed more than six months after response to the last platinum-based chemotherapy. Niraparib is currently marketed by GSK as ZEJULA.5

About Metastatic Castration-Resistant Prostate Cancer
Metastatic castration-resistant prostate cancer characterizes cancer that no longer responds to androgen deprivation therapy and has spread to other parts of the body. The most common metastatic sites are bones, followed by lymph nodes, lungs and liver.6 Prostate cancer is the second most common cancer in men worldwide, behind lung cancer.2 More than one million men around the world are diagnosed with prostate cancer each year.7 Patients with mCRPC and HRR gene alterations have a worse prognosis than those without HRR alterations.8

On February 14, 2022 Roivant Sciences reported that has spawned another Vant (Press release, Roivant Sciences, FEB 14, 2022, View Source [SID1234608336]). The latest addition to the clan is Hemavant, a biotech that starts life with a former Eisai drug and plans to start a study in patients with myelodysplastic syndromes (MDS) this year.

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Hemavant is developing RVT-2001, the small-molecule modulator of splicing factor 3B subunit 1 that Roivant licensed from Eisai late last year. Eisai, working with its H3 Biomedicine subsidiary, took the oral candidate into a phase 1 clinical trial in 2016 but saw no complete or partial responses in the first 84 patients enrolled in the study of patients with MDS and other blood cancers.

Work stalled on the candidate after the 2019 data drop, with Roivant saying in January that the number of subjects treated with RVT-2001 still stands at "over 80." Yet, Roivant sees promise in some of the data generated by Eisai, leading it to license the asset and narrow the focus of the program.

Eisai enrolled patients with acute myeloid leukemia, chronic myelomonocytic leukemia and lower- and higher-risk MDS in its phase 1 study. In that population, the lack of responses was a blow, but Roivant has zeroed in on another endpoint that suggests RVT-2001 may have a future in lower-risk, transfusion-dependent MDS patients.

RELATED: Roivant ditches plan to reacquire Immunovant, invests $200M

Thirty percent of the 19 lower-risk MDS patients treated with RVT-2001, formerly known as H3B 8800, gained red blood cell transfusion independence. Most of the patients had previously received Bristol Myers Squibb’s Revlimid, hypomethylating agents or both therapies.

Based on the signal, Hemavant is developing RVT-2001 as an oral therapy for transfusion-dependent anemia in patients with lower-risk MDS. A phase 1/2 clinical trial is set to start in the first half of the year.

Roivant has paid Eisai $8 million in cash and $7 million in stock for the global rights to the candidate. As RVT-2001 advances, Roivant will pay up to $65 million in development and regulatory milestones in the first indication plus up to $18 million in additional indications. The deal also features up to $295 million in commercial milestones and a tiered high single-digit to sub-teens royalty.

On February 14, 2022 Nykode Therapeutics AS (Euronext Growth (Oslo): NYKD), a clinical-stage biopharmaceutical company dedicated to the discovery and development of vaccines and novel immunotherapies, reported that its Chief Executive Officer, Michael Engsig, and Chief Innovation and Strategy Officer, Agnete Fredriksen, will present and provide a corporate update at the SVB Leerink 2022 Global Healthcare Conference on February 18, 2022 at 2.00 p.m. CET/ 8.00 a.m. EST and are available for 1:1 investor meetings (Press release, Nykode Therapeutics, FEB 14, 2022, View Source [SID1234608062]).

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An updated corporate presentation will be available in the Investors section of the Company’s website at 7:00 a.m. CET on February 18, 2022 at www.nykode.com/investors. The live and archived webcast of the presentation can be accessed in the Investors section of the Company’s website here.